PRODUCT MONOGRAPH. ziprasidone capsules. 20, 40, 60, and 80 mg. Antipsychotic Agent

Transcription

1 PRODUCT MONOGRAPH Pr ZELDOX ziprasidone capsules 20, 40, 60, and 80 mg Antipsychotic Agent Pfizer Canada Inc Trans-Canada Highway Kirkland, Québec H9J 2M5 Date of Preparation: 06 May 2016 Submission Control No: TM Pfizer Products Inc. Pfizer Canada Inc., Licensee Pfizer Canada Inc ZELDOX (ziprasidone) - Product Monograph Page 1 of 62

2 Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION... 3 SUMMARY PRODUCT INFORMATION... 3 INDICATIONS AND CLINICAL USE... 3 CONTRAINDICATIONS... 4 WARNINGS AND PRECAUTIONS... 5 ADVERSE REACTIONS DRUG INTERACTIONS DOSAGE AND ADMINISTRATION OVERDOSAGE ACTION AND CLINICAL PHARMACOLOGY STORAGE AND STABILITY DOSAGE FORMS, COMPOSITION AND PACKAGING PART II: SCIENTIFIC INFORMATION PHARMACEUTICAL INFORMATION CLINICAL TRIALS DETAILED PHARMACOLOGY TOXICOLOGY REFERENCES PART III: CONSUMER INFORMATION ZELDOX (ziprasidone) - Product Monograph Page 2 of 62

3 Pr ZELDOX ziprasidone capsules PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Administration Dosage Form / Strength Oral Capsules 20, 40, 60, and 80 mg All Nonmedicinal Ingredients Lactose monohydrate, magnesium stearate, pregelatinized starch, and gelatin capsules. INDICATIONS AND CLINICAL USE Schizophrenia ZELDOX (ziprasidone hydrochloride) is indicated for the treatment of schizophrenia and related psychotic disorders. The prescriber should consider the finding of ziprasidone s greater capacity to prolong the QT/QTc interval compared to other antipsychotic drugs (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS). The efficacy of ziprasidone was established in short-term (4- and 6-week) controlled trials of schizophrenic inpatients (see Part II: CLINICAL TRIALS). ZELDOX has been shown to be effective in maintaining clinical improvement during long-term therapy (1-year). The physician who elects to use ZELDOX for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. Bipolar Disorder ZELDOX (ziprasidone hydrochloride) is indicated for the treatment of acute manic or mixed episodes associated with bipolar disorder. The prescriber should consider the finding of ziprasidone s greater capacity to prolong the QT/QTc interval compared to other antipsychotic drugs (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS). The efficacy of ziprasidone in acute mania was established in 2 placebo-controlled, double-blind, 3-week studies which compared ziprasidone with placebo and 1 double-blind, 12-week (3-week placebocontrolled, active comparator acute phase and 9-week active comparator phase) study which compared ziprasidone to haloperidol and placebo, in patients meeting DSM-IV criteria for Bipolar I Disorder (see Part II: CLINICAL TRIALS). ZELDOX (ziprasidone) - Product Monograph Page 3 of 62

4 The effectiveness of ZELDOX for longer-term use and for prophylactic use in mania has not been systematically evaluated in controlled clinical trials. Therefore, physicians who elect to use ziprasidone for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient. Geriatrics (>65 years of age): ZELDOX is not indicated in elderly patients with dementia (see WARNINGS AND PRECAUTIONS, Serious Warnings and Precaution Box and ACTION AND CLINICAL PHARMACOLOGY, Special Populations). Caution should be used when treating geriatric patients with ZELDOX. See ACTION AND CLINICAL PHARMACOLOGY, Special Populations), and DOSAGE AND ADMINISTRATION sections. Pediatrics (<18 years of age): The safety and efficacy of ZELDOX in children under the age of 18 years have not been established and its use is not recommended in this population (see WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics). CONTRAINDICATIONS QT Prolongation: Because of ziprasidone s dose-related prolongation of the QT interval and the known association of fatal arrhythmias with QT prolongation by some other drugs, ziprasidone is contraindicated in patients with: known history of QT prolongation (including congenital long QT syndrome); recent acute myocardial infarction; or uncompensated heart failure (see WARNINGS AND PRECAUTIONS). Pharmacokinetic/pharmacodynamic studies between ziprasidone and other drugs that prolong the QT interval have not been performed. An additive effect of ziprasidone and other drugs that prolong the QT interval cannot be excluded. Therefore, ziprasidone should not be given with dofetilide, sotalol, quinidine, other Class Ia and III anti-arrhythmias, mesoridazine, thioridazine, chlorpromazine, droperidol, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol or tacrolimus. Ziprasidone is also contraindicated with drugs that have demonstrated QT prolongation as one of their pharmacodynamic effects and have this effect described in their respective Product Monograph as a contraindication or a warning (see WARNINGS AND PRECAUTIONS). Patients who are hypersensitive to ziprasidone or to any ingredient in the formulation or component of the container. For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING. ZELDOX (ziprasidone) - Product Monograph Page 4 of 62

5 WARNINGS AND PRECAUTIONS Serious Warnings and Precautions Increased Mortality in Elderly Patients with Dementia Elderly patients with dementia treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of 13 placebo-controlled trials with various antipsychotics (modal duration of 10 weeks) in these patients showed a mean 1.6-fold increase in the death rate in the drug-treated patients. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature (see WARNINGS AND PRECAUTIONS, Special Populations, Use in Geriatric Patients with Dementia). QT Prolongation (see also CONTRAINDICATIONS): ZELDOX (ziprasidone hydrochloride) is associated with moderate QT/QTC interval prolongation, as described in the subsections below. Recommendations regarding Risk Factors for QT prolongation Many drugs that cause QT/QTc prolongation are suspected to increase the risk of a rare, potentially fatal polymorphic ventricular tachyarrhythmia known as torsades de pointes. Generally, the risk of torsades de pointes increases with magnitude of the QT/QTc prolongation produced by the drug. Torsades may be asymptomatic or experienced by the patient as dizziness, palpitations, syncope or seizures. If sustained, torsades de pointes can progress to ventricular fibrillation and sudden cardiac death. As per Health Canada s QT/QTc Guidelines, in the general population, certain circumstances may increase the risk of the occurrence of torsades de pointes in association with the use of drugs that prolong the QT/QTc interval, including (1) bradycardia; (2) electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, or hypocalcemia); (3) concomitant use of other drugs that prolong the QT/QTc interval; (4) presence of congenital prolongation of the QT interval; (5) family history of sudden cardiac death at <50 years; (6) personal history of cardiac disease or arrhythmias; (7) acute neurological events, e.g., stroke; (8) being female or 65 years of age or older; (9) nutritional deficits e.g., eating disorders; (10) diabetes mellitus. Therefore: Ziprasidone should not be used in combination with other drugs that are known to prolong the QT/QTc interval (see CONTRAINDICATIONS). Additionally, clinicians should be alert to the identification of other drugs that have been consistently observed to prolong the QT/QTc interval. Such drugs should not be prescribed with ziprasidone. Ziprasidone should also not be used in patients with congenital long QT syndrome, or in patients with a history of cardiac arrhythmias, with recent acute myocardial infarction, or with uncompensated heart failure (see CONTRAINDICATIONS). ZELDOX (ziprasidone) - Product Monograph Page 5 of 62

6 If patients with stable cardiac disease are treated, an ECG review should be considered before treatment is started. Persistently prolonged QT/QTc intervals may also increase the risk of further prolongation and arrhythmia, but it is not clear that routine screening ECG measures are effective in detecting such patients. Rather, if cardiac symptoms, such as palpitations, vertigo, syncope or seizures occur then the possibility of a malignant cardiac arrhythmia should be considered and a cardiac evaluation including an ECG should be performed. If the QTc interval for a patient is >500 msec, then it is recommended that the treatment be stopped. It is recommended that patients being considered for ziprasidone treatment who are at risk for significant electrolyte disturbances (e.g., diuretic therapy, protracted diarrhea or vomiting, water intoxication, eating disorder, and alcoholism), have baseline serum potassium and magnesium measurements performed and levels corrected if necessary. Hypokalemia (and/or hypomagnesemia) may increase the risk of QT prolongation and arrhythmia. It is essential to periodically monitor serum electrolytes in patients for whom diuretic therapy is introduced during ziprasidone treatment. Patients receiving treatment with drugs that prolong the QT/QTc interval should be counselled appropriately, regarding risk factors, symptoms suggestive of arrhythmia and risk management strategies. Description of Data: 1) Studies Specifically Designed to Assess QT Prolongation a) Comparative study ( ): Six antipsychotics A study directly comparing the QT/QTc prolonging effect of ziprasidone with several other drugs effective in the treatment of schizophrenia was conducted in patient volunteers (n=28-35 per drug). In the first phase of the trial, ECGs were obtained at the time of maximum plasma concentration when the drug was administered alone. In the second phase of the trial, ECGs were obtained at the time of maximum plasma concentration while the drug was co-administered with an inhibitor of the CYP450 metabolism of the drug. In the first phase of the study, the mean change in QTc from baseline was calculated for each drug, using a sample-based correction that makes adjustments for the effect of heart rate on the QT interval. The mean increase in QTc from baseline for ziprasidone (baseline correction) at 160 mg/day was 15.9 msec, which was approximately 9 to 14 msec greater than for four of the comparator drugs (haloperidol at 15 mg/day [7.1 msec], quetiapine at 750 mg/day [5.7 msec], risperidone at 16 mg/day [3.6 msec], and olanzapine at 20 mg /day [1.7 msec], but was approximately 14 msec less than the prolongation observed for thioridazine at 300 mg/day [30.1 msec]. In the second phase of the study, the effect of ziprasidone on QTc length (16.6 msec) was not augmented by the presence of a metabolic inhibitor (ketoconazole 200 mg BID). The mean increase for the other comparator drugs was haloperidol [13.3 msec], quetiapine [8.0 msec], olanzapine [3.0 msec], and risperidone [2.6 msec], compared to thioridazine [29.6 msec]. ZELDOX (ziprasidone) - Product Monograph Page 6 of 62

7 b) QT Effects at 2x maximum recommended ziprasidone dose A study examining the effect of 3 doses of orally administered ziprasidone (including twice the recommended clinical dose, n=29) and haloperidol (the highest dose level was comparably high, n=30) on the QTc interval was conducted in clinically stable patients with schizophrenia and schizoaffective disorder. The study comprised 4 consecutive periods, including drug tapering (phase 1), wash out (phase 2), drug therapy (phase 3) followed by the study drug wash out and initiation of outpatient drug therapy (phase 4). Serial baseline electrocardiograms (ECGs) were collected under controlled conditions on the last day (day 0) of period 2 at times matched to those collected during study drug administration (phase 3) at the time of estimated peak drug exposure. At each steady-state dose level, three ECGs and a pharmacokinetic sample were collected at the predicted time of peak exposure to administered drug (Tmax). One of the three ECGs was collected at Tmax and the other two were collected one hour on either side of Tmax. The mean increase in QTc from baseline for ziprasidone at 40 mg/day was 4.5 msec, and at 160 mg/day was 19.5 msec (comparable to the study described above). A further increase in dose to 320 mg/day (twice the maximum recommended clinical dose) led to an increase in QTc of 22.5 msec, which was only 3 msec more than after 160 mg/day in this study, suggesting a plateau. In comparison, there was no mean QTc increase apparent at the lowest haloperidol dose (2.5 mg/day). At the 2 higher doses of haloperidol, (15 and 30 mg/day), mean QTc increases ranged from 6.6 to 7.2 msec. No subject in either treatment group experienced a QTc interval 450 msec or an increase from baseline of 75 msec. 2) Data from Non-QT specific ziprasidone studies In placebo-controlled trials, ziprasidone increased the QTc interval compared to placebo by approximately 10 msec at the highest recommended daily dose of 160 mg, which was the basis for subsequent QT-specific studies. The clinical trial data for ziprasidone did not reveal an excess risk of mortality for ziprasidone compared to other antipsychotic drugs or placebo. Electrocardiogram readings revealing QTc intervals exceeding the potentially clinically relevant threshold of 500 msec in clinical trials with ziprasidone occurred in: 2/3266 (0.06%) patients receiving ZELDOX (ziprasidone hydrochloride) and 1/538 (0.19%) patients receiving placebo. One patient had a history of prolonged QTc and a screening measurement of 489 msec; QTc was 503 msec during ziprasidone treatment. The other patient, who was receiving ziprasidone for more than 6.5 years without interruption, had a QTc of 503 msec at week 189, and 435 msec 19 weeks later, while maintained on the same oral dose of ziprasidone. There were confounding factors that contributed to the occurrence of these cases. 3) Post-Marketing Data (see also ADVERSE EVENTS, Post-Marketing) Torsades de Pointes There have been rare post-marketing reports of torsades de pointes (in the presence of multiple confounding factors) (see ADVERSE REACTIONS; Post-Market Adverse Drug Reactions). Torsades de pointes have not been observed in association with the use of ziprasidone at recommended doses in clinical trials, but experience is too limited to rule out increased risk. Analysis of Post-Marketing Data In view of the clinical trial data demonstrating a moderate QT prolongation effect of ZELDOX, a review ZELDOX (ziprasidone) - Product Monograph Page 7 of 62

8 of 5-year, post-marketing spontaneous data from the FDA AERS database was conducted using a set of heart-related search terms. Small elevations in spontaneous reporting rates were observed for ziprasidone compared with two other atypical antipsychotics, for both fatal cases, and "all" cases (i.e., fatal plus non-fatal). Accumulated case reports should not be used as a basis for determining the incidence of a reaction or estimating risk for a particular product, as neither the total number of reactions occurring, nor the number of patients exposed to the health product is known. Because of the multiple factors that influence reporting, quantitative comparisons of health product safety cannot be made from the data. Comparison of reporting rates cannot be employed to confirm or refute a hypothesis, due to well-known, inherent limitations with spontaneous reporting of adverse events. General Body Temperature Regulation Disruption of the body s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing ziprasidone for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration. Carcinogenesis and Mutagenesis For animal data, see Part II: TOXICOLOGY. Cardiovascular See also CONTRAINDICATIONS; and WARNINGS AND PRECAUTIONS, QT Prolongation. Orthostatic Hypotension Ziprasidone may induce orthostatic hypotension associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its α 1 -adrenergic antagonist properties. Syncope was reported in 0.6% (22/3834) of the patients treated with ziprasidone. Ziprasidone should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease or conditions which would predispose patients to hypotension (dehydration, hypovolemia and treatment with antihypertensive medications). Patients with a history of clinically significant cardiac disorders were excluded from the trials. Dependence/Tolerance ZELDOX has not been systematically studied, in animals or humans, for its potential for abuse, tolerance ZELDOX (ziprasidone) - Product Monograph Page 8 of 62

9 or physical dependence. While clinical trials did not reveal any tendency for drug-seeking behaviour, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which ZELDOX will be misused, diverted and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of ZELDOX misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behaviour). Endocrine and Metabolism Hyperglycemia As with some other antipsychotics, hyperglycemia, exacerbation of pre-existing diabetes, and diabetic coma have been reported very rarely during the use of ZELDOX. However, no causal relationship with ZELDOX has been established (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions). Diabetic ketoacidosis (DKA) has occurred in patients with no reported history of hyperglycemia. Patients should have baseline and periodic monitoring of blood glucose and body weight. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, and that there is no data in drug-naïve patients, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies, which did not include ZELDOX, suggest an increased risk of treatmentemergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Because ZELDOX was not marketed at the time these studies were performed, it is not known if ZELDOX is associated with this increased risk. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia, including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Hyperprolactinemia As with other drugs that antagonize dopamine D 2 receptors and/or serotonin 5-HT 2 receptors, ZELDOX may elevate prolactin levels in humans. Elevations associated with ZELDOX treatment are generally mild and may decline during administration. Increased prolactin levels were also observed in animal studies with this compound, and were associated with an increase in mammary gland neoplasia in mice; a similar effect was not observed in rats (see ZELDOX (ziprasidone) - Product Monograph Page 9 of 62

10 TOXICOLOGY, Carcinogenicity). Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactindependent in vitro, ZELDOX should only be administered to patients with previously detected breast cancer if the benefits outweigh the potential risks. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds, the clinical significance of elevated serum prolactin levels is unknown for most patients. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone mineral density in both female and male subjects. Caution should be exercised when considering ziprasidone treatment in patients with pituitary tumors. Neither clinical studies nor epidemiological studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans. The available evidence is considered too limited to be conclusive at this time. Gastrointestinal Patients should be advised of the risk of severe constipation during ZELDOX treatment, and that they should tell their doctor if constipation occurs or worsens, as they may need laxatives (see ADVERSE REACTIONS, Post Market Adverse Drug Reactions). Genitourinary Priapism Rare cases of priapism have been reported with antipsychotic use, such as ZELDOX. This adverse reaction, as with other psychotropic drugs, did not appear to be dose-dependent and did not correlate with duration of treatment. The likely mechanism of action of priapism is a relative decrease in sympathetic tone. Severe priapism may require surgical intervention. Hematologic Venous Thromboembolism Venous thromboembolism (VTE), including fatal pulmonary embolism, has been reported with antipsychotic drugs, including ZELDOX, in case reports and/or observational studies. When prescribing ZELDOX, all possible risk factors for VTE should be identified before and during treatment with ZELDOX and preventive measures undertaken. Hemic and Lymphatic System Neutropenia, granulocytopenia, and agranulocytosis have been reported during antipsychotic use. Agranulocytosis has been reported (see ADVERSE REACTIONS, Post Market Adverse Drug Reactions). Therefore, it is recommended that patients have their complete blood count (CBC) tested prior to starting ZELDOX and then periodically throughout treatment. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) ZELDOX (ziprasidone) - Product Monograph Page 10 of 62

11 and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and ZELDOX should be discontinued at the first sign of decline in WBC, in the absence of other causative factors. Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1 x 10 9 /L) should discontinue ZELDOX and have their WBC followed until recovery. Hepatic See WARNINGS AND PRECAUTIONS, Special Populations, Hepatic Impairment. Neurologic Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as NMS has been reported in association with the administration of antipsychotic drugs, including ZELDOX. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.), and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs including ZELDOX and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. Tardive Dyskinesia (TD) A syndrome consisting of potentially irreversible, involuntary and disabling dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the tardive dyskinesia syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to ZELDOX (ziprasidone) - Product Monograph Page 11 of 62

12 develop the tardive dyskinesia syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia, and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself however may suppress (or partially suppress) the signs and symptoms of the tardive dyskinesia syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the tardive dyskinesia syndrome is unknown. Given these considerations, ZELDOX should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who 1) suffer from a chronic illness that is known to respond to antipsychotic drugs, and 2) for whom alternative, equally effective but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on ZELDOX, drug discontinuation should be considered. However, some patients may require treatment with ZELDOX despite the presence of the tardive dyskinesia syndrome. Potential Effect on Cognitive and Motor Performance Somnolence was a commonly reported adverse event in patients treated with ZELDOX. In the 4- and 6- week placebo-controlled trials in patients with schizophrenia, somnolence was reported in 14% of patients on ziprasidone compared to 7% of patients on placebo (see ADVERSE REACTIONS). Since ziprasidone has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about performing activities requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating hazardous machinery, until they are reasonably certain that ziprasidone therapy does not affect them adversely. Seizures During clinical trials, seizures occurred in 0.4% of patients treated with ziprasidone. There were confounding factors that may have contributed to the occurrence of seizures in many of these cases. Nevertheless, as with other antipsychotic drugs, ziprasidone should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer s dementia. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older. ZELDOX (ziprasidone) - Product Monograph Page 12 of 62

13 Serotonin Syndrome Serotonin syndrome is a rare and potentially life-threatening event in which signs and symptoms include high fever, seizures, arrhythmias, and unconsciousness observed in patients taking multiple serotonergic agents or who have had considerable exposure to a single serotonin-augmenting drug. In isolated cases, there have been reports of serotonin syndrome temporally associated with the therapeutic use of ziprasidone in combination with other serotonergic medicinal products such as SSRIs (see ADVERSE REACTIONS, Post Market Adverse Drug Reactions). The features of serotonin syndrome can include confusion, agitation, fever, sweating, ataxia, hyperreflexia, myoclonus and diarrhea,hyperthermia, rigidity, and autonomic instability with possible rapid fluctuations of vital signs and symptoms can progress to delirium and coma. Management of serotonin syndrome includes withdrawal of the offending medication and supportive care for mild cases; hospitalization is required for moderate to severe cases Psychiatric Suicide The possibility of a suicide attempt is inherent in psychotic illness; thus, close supervision and appropriate clinical management of high-risk patients should accompany drug therapy. Prescriptions for ZELDOX should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Renal Dose adjustments are not required for patients with renal impairment (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Insufficiency). Skin Severe Cutaneous Adverse Reactions Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported with ziprasidone exposure. DRESS consists of a combination of three or more of the following: cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, lymphadenopathy and one or more systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and pericarditis. Other severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, have been reported with ziprasidone exposure (see ADVERSE REACTIONS, Post Market Adverse Drug Reactions). Severe cutaneous adverse reactions are sometimes fatal. Discontinue ziprasidone if severe cutaneous adverse reactions occur. ZELDOX (ziprasidone) - Product Monograph Page 13 of 62

14 Rash In pre-marketing trials with ziprasidone, about 5% of patients developed rash (173/3834) and/or urticaria (12/3834), with discontinuation in about one-sixth of these cases. The occurrence of rash was related to dose of ziprasidone, although the finding might also be explained by the longer exposure time in the higher dose patients. Several patients with rash had signs and symptoms of associated systemic illness, e.g., elevated white blood cells (WBC). Most patients improved promptly with adjunctive treatment with antihistamines or steroids and/or upon discontinuation of ziprasidone, and all patients experiencing these events were reported to recover completely. Upon appearance of rash for which an alternative etiology cannot be identified, ziprasidone should be discontinued. Special Populations Pregnant Women There are no adequate and well-controlled studies in pregnant women. Women of childbearing potential receiving ziprasidone should therefore be counselled on the need to use an effective method of contraception during treatment with ZELDOX. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant. ZELDOX should not be used during pregnancy unless the expected benefits to the mother markedly outweigh the potential risks to the fetus. Teratogenic effects In animal studies, ziprasidone demonstrated developmental toxicity, including possible teratogenic effects at doses similar to human therapeutic doses. When ziprasidone was administered to pregnant rabbits during the period of organogenesis, an increased incidence of fetal structural abnormalities (ventricular septal defects and other cardiovascular malformations and kidney alterations) was observed at a dose of 30 mg/kg/day (3 times the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m 2 basis). There was no evidence to suggest that these developmental effects were secondary to maternal toxicity. The developmental no-effect dose was 10 mg/kg/day (equivalent to the MRHD on an mg/m 2 basis). In rats, embryofetal toxicity (decreased fetal weights, delayed skeletal ossification) was observed following administration of 10 to 160 mg/kg/day (0.5 to 8 times the MRHD on a mg/m 2 basis) during organogenesis or throughout gestation, but there was no evidence of teratogenicity. Doses of 40 and 160 mg/kg/day (2 and 8 times the MRHD on a mg/m 2 basis) were associated with maternal toxicity. The developmental no-effect dose was 5 mg/kg/day (0.2 times the MRHD on a mg/m 2 basis). There was an increase in the number of pups born dead and a decrease in postnatal survival through the first 4 days of lactation among the offspring of female rats treated during gestation and lactation with doses of 10 mg/kg/day (0.5 times the MRHD on a mg/m 2 basis) or greater. Offspring developmental delays and neurobehavioral functional impairment were observed at doses of 5 mg/kg/day (0.2 times the MRHD on a mg/m 2 basis) or greater. A no-effect level was not established for these effects. ZELDOX (ziprasidone) - Product Monograph Page 14 of 62

15 Non teratogenic effects Neonates exposed to antipsychotic drugs (including ZELDOX) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been selflimited, in other cases neonates have required intensive care unit support and prolonged hospitalization. ZELDOX should not be used during pregnancy unless the expected benefits to the mother markedly outweigh the potential risks to the fetus. Labor and Delivery The effect of ZELDOX on labor and delivery in humans is not known. Nursing Women It is not known whether, and if so in what amount, ziprasidone or its metabolites are excreted in human milk. It is recommended that women taking ZELDOX should not breast-feed. Pediatrics (< 18 years of age) The safety and efficacy of ZELDOX in children under the age of 18 years have not been established and its use is not recommended. Weight gain has been observed with atypical antipsychotic use in pediatric and adolescent patient populations. Independent of any drug-specific effects, weight gain can be associated with adverse changes in other metabolic parameters (e.g., glucose and lipid metabolism). Abnormal childhood weight and metabolic status can have adverse effects on cardiovascular outcomes in adulthood. Weight gain and adverse effects on other metabolic parameters associated with atypical antipsychotics can be more frequent or more severe in pediatric and adolescent patients than in the adult patients. The following adverse events in the two studies in pediatrics are of note because they are not typical of the adult population treated with ziprasidone: abnormally decreased bicarbonate values; elevations in testosterone, elevations in insulin, total neutrophils, monocytes and ALT; fatigue; abdominal pain, insomnia; restlessness. There are also adverse events of note due to a greater incidence rate compared to adults, or a greater differential over placebo: blurred vision; extrapyramidal symptoms (aggregated); sedation/somnolence; nausea; vomiting; and elevations in serum prolactin (See ADVERSE REACTIONS, Adverse Drug Reactions in Pediatrics). The long-term safety, including cardiometabolic effects and effects on growth, maturation and behavioural development in patients under 18 years of age has not been systematically evaluated. The ZELDOX pediatric study in schizophrenia was terminated by Pfizer due to lack of efficacy (Placebocontrolled study A , and open-label extension 1135) ZELDOX (ziprasidone) - Product Monograph Page 15 of 62

16 Geriatrics (> 65 years of age) The number of patients 65 years or older with schizophrenia or related disorders, exposed to ZELDOX during clinical trials was limited (n=109). In general, there was no indication of any different tolerability of ziprasidone or for reduced clearance of ziprasidone in the elderly compared to younger adults. Nevertheless, geriatric patients generally have decreased cardiac, hepatic and renal function, and more frequent use of concomitant medication. The presence of multiple factors that might increase the pharmacodynamic response to ziprasidone, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful monitoring during the initial dosing period for elderly patients. Use in Geriatric Patients with Dementia Overall Mortality Elderly patients with dementia treated with atypical antipsychotic drugs have an increased mortality compared to placebo in a meta-analysis of 13 controlled trials of various atypical antipsychotic drugs. ZELDOX is not indicated in elderly patients with dementia (e.g., dementiarelated psychosis) (see WARNINGS AND PRECAUTIONS, Serious Warnings and Precautions). Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer s dementia. Ziprasidone and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. Cerebrovascular Adverse Events (CVAEs), including Stroke in Elderly Patients with Dementia In placebo-controlled trials with some atypical antipsychotics, there was a higher incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. ZELDOX is not indicated for the treatment of patients with dementia (e.g., dementia-related psychosis). (see WARNINGS AND PRECAUTIONS, Serious Warnings and Precautions). Use in Patients with Concomitant Illness Ziprasidone has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical studies. Because of the risks of QT/QTc prolongation and orthostatic hypotension with ziprasidone, caution should be observed in cardiac patients (see CONTRAINDICATIONS, as well as WARNINGS AND PRECAUTIONS, QT Prolongation and Cardiovascular, Orthostatic Hypotension). ZELDOX (ziprasidone) - Product Monograph Page 16 of 62

17 Hepatic Impairment In patients with hepatic insufficiency, lower doses should be considered (see DOSAGE AND ADMINISTRATION, Hepatic Impairment and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Insufficiency). Renal Impairment Dose adjustments are not required for patients with renal impairment (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Insufficiency). Lactose ZELDOX capsules contain lactose. This should be considered when prescribing to patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption. Monitoring and Laboratory Tests Patients being considered for ziprasidone treatment that are at risk of significant electrolyte disturbances should have baseline serum potassium and magnesium measurements. Low serum potassium and magnesium should be repleted before proceeding with treatment. Patients who are started on diuretics during ziprasidone therapy need periodic monitoring of serum potassium and magnesium. Ziprasidone should be discontinued in patients who are found to have persistent QTc measurements >500 msec (see WARNINGS AND PRECAUTIONS, QT Prolongation). ADVERSE REACTIONS Adverse Drug Reaction Overview The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Clinical Trial Adverse Drug Reactions Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. Adverse Events Observed in Short-Term, Placebo-Controlled Trials The following findings are based on a pool of two 6-week, and two 4-week placebo-controlled trials for schizophrenia and a pool of three 3-week flexible dose trials for bipolar mania in which ziprasidone was administered in doses ranging from 10 to 200 mg/day. ZELDOX (ziprasidone) - Product Monograph Page 17 of 62

18 Schizophrenia Adverse Events Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials A total of 4.1% (29/702) of patients treated with ZELDOX (ziprasidone hydrochloride) in short-term, placebo-controlled studies discontinued treatment due to an adverse event, compared with 2.2% (6/273) on placebo and 8.2% (7/85) on the active control drug. The most common event associated with dropout was rash, including 7 dropouts for rash among ziprasidone patients (1%) compared to no placebo patients (see WARNINGS AND PRECAUTIONS, SKIN, Rash). Adverse Events Occurring at an Incidence of 1% or more in Short-Term, Placebo-Controlled Trials (up to 6 weeks) Table 1 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy (up to 6 weeks) in predominantly schizophrenic patients, including only those events that occurred in 1% or more of patients treated with ziprasidone and for which the incidence in patients treated with ziprasidone was greater than the incidence in placebo-treated patients. Table 1. Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled Trials Schizophrenia Body System Percentage of patients reporting ZELDOX (n = 702) Placebo (n = 273) Body as a Whole Asthenia 5 3 Accidental Injury 4 2 Chest Pain 3 2 Cardiovascular Tachycardia 2 1 Postural Hypotension 1 0 Digestive Nausea 10 7 Constipation 9 8 Dyspepsia 8 7 Diarrhea 5 4 Dry Mouth 4 2 Anorexia 2 1 Musculoskeletal Myalgia 1 0 Nervous Extrapyramidal Symptoms* 14 8 Somnolence 14 7 Akathisia 8 7 Dizziness** 8 6 Respiratory Respiratory Tract Infection 8 3 Rhinitis 4 2 Cough Increased 3 1 Skin and Appendages Rash 4 3 Fungal Dermatitis 2 1 Special Senses Abnormal Vision 3 2 * Extrapyramidal Symptoms includes the following adverse event terms: extrapyramidal syndrome, hypertonia, dystonia, dyskinesia, hypokinesia, tremor, paralysis and twitching. None of these adverse events occurred individually at an incidence greater than 5% in schizophrenia trials. ** Dizziness includes the adverse event terms dizziness and lightheadedness ZELDOX (ziprasidone) - Product Monograph Page 18 of 62

19 Explorations for interactions on the basis of gender did not reveal any clinically meaningful differences in the adverse event occurrence on the basis of this demographic factor. Commonly Observed Adverse Events in Short-Term, Placebo-Controlled Trials In the schizophrenia studies, the most commonly observed adverse events associated with the use of ziprasidone (incidence of 5% or greater) and observed at a rate on ziprasidone at least twice that of placebo were somnolence (14%), extrapyramidal symptoms (14%), and respiratory tract infection (8%). Dose Dependency of Adverse Events in Short-Term, Placebo-Controlled Trials An analysis for dose response in the schizophrenia 4-study pool revealed an apparent relation of adverse event to dose for the following events: asthenia, postural hypotension, anorexia, dry mouth, increased salivation, arthralgia, anxiety, dizziness, dystonia, hypertonia, somnolence, tremor, rhinitis, rash, and abnormal vision. Extrapyramidal Symptoms (EPS) - Schizophrenia The incidence of reported EPS for ziprasidone-treated patients in the short-term, placebo-controlled trials was 14% vs. 8% for placebo. Medications to treat EPS and movement disorders were allowed; but if clinically meaningful movement disorder side effects were observed by the clinician or volunteered by the subject, or if a clinically meaningful movement disorder, present at screening, increased in severity or required the administration of anticholinergics or propanolol, these symptoms and their severity were recorded as adverse event. Objectively collected data from those trials on the Simpson Angus Rating Scale (for EPS) and the Barnes Akathisia Scale (for akathisia) did not generally show a difference between ziprasidone and placebo. Table 2. Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Events Incidence in Short-Term, Schizophrenia Placebo-Controlled Trials Percentage of Subjects Reporting Event Extrapyramidal Symptoms Zeldox N=702 Placebo N=273 Dystonic events 1 4.0% 2.2% Parkinsonism events % 5.1% Akathisia events 3 8.4% 7.0% Dyskinetic events 4 1.9% 2.9% Residual events 5 0.3% 0.4% Any extrapyramidal event 21.7% 15% 1 Patients with the following COSTART terms were counted in this category: dystonia, oculogyric crisis 2 Patients with the following COSTART terms were counted in this category: abnormal gait, akinesia, cogwheel rigidity, extrapyramidal syndrome, hypokinesia, muscular hypertonia, tremor 3 Patients with the following COSTART terms were counted in this category: akathisia 4 Patients with the following COSTART terms were counted in this category: dyskinesia, paralysis, tardive dyskinesia 5 Patients with the following COSTART terms were counted in this category: twitching ZELDOX (ziprasidone) - Product Monograph Page 19 of 62

20 Dystonia Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Vital Sign Changes ZELDOX is associated with orthostatic hypotension (see WARNINGS AND PRECAUTIONS, Cardiovascular, Orthostatic Hypotension). ECG Changes Ziprasidone is associated with an increase in the QTc interval (see WARNINGS AND PRECAUTIONS, QT Prolongation). In schizophrenia trials, ziprasidone was associated with a mean increase in heart rate of 1.4 beats per minute compared to a 0.2 beats per minute decrease among placebo patients. Weight Gain The proportions of patients meeting a weight gain criterion of >7% of body weight were compared in a pool of four 4- and 6-week placebo-controlled schizophrenia clinical trials, revealing a statistically significantly greater incidence of weight gain for ziprasidone (10%) compared to placebo (4%). A median weight gain of 0.5 kg was observed in ziprasidone patients compared to no median weight change in placebo patients. In this set of clinical trials, weight gain was reported as an adverse event in 0.4% of ziprasidone and 0.4% of placebo patients. During long-term therapy with ziprasidone, a categorization of patients at baseline on the basis of body mass index (BMI) revealed the greatest mean weight gain and highest incidence of clinically significant weight gain (>7% of body weight) in patients with low BMI (<23) compared to normal (23-27) or overweight patients (>27). There was a mean weight gain of 1.4 kg for those patients with a low baseline BMI, no mean change for patients with a normal BMI, and a 1.3 kg mean weight loss for patients who entered the program with a high BMI. Less Common Clinical Trial Adverse Events (<1%) Schizophrenia Other Adverse Events Observed During the Pre-marketing Evaluation of Oral ZELDOX All reported treatment-emergent events are included except those already listed in Table 1 or in other sections. It is important to emphasize that, although the events reported occurred during treatment with ZELDOX capsules, they were not necessarily caused by the therapy. The adverse events are categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); ZELDOX (ziprasidone) - Product Monograph Page 20 of 62